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  • Review Article
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AMPK as a mediator of tissue preservation: time for a shift in dogma?

Nature Reviews Endocrinology (2024)Cite this article

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Abstract

Ground-breaking discoveries have established 5′-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK’s role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

Key points

  • AMPK is traditionally viewed as a predominantly anti-anabolic enzyme that mitigates the inhibition of protein synthesis.

  • Emerging evidence from preclinical models suggests that activating AMPK could be a viable strategy to improve muscle and adipose tissue maintenance during wasting conditions, such as cancer cachexia.

  • AMPK’s ability to ensure sufficient ATP levels by regulating mitochondrial function and insulin sensitivity supports cellular homeostasis and survival during cancer cachexia.

  • Direct and indirect AMPK-activating strategies in preclinical cachexia models resulted in increased anabolism and attenuated muscle and adipose tissue atrophy.

  • The benefits of AMPK are probably not limited to cancer cachexia but can be found in other metabolic conditions that also involve tissue wasting, such as sarcopenia or congenital muscular dystrophies.

  • AMPK could be a target for the design of strategies that address the unmet clinical need for treatment of wasting conditions, such as cancer cachexia.

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Fig. 1: Activating and inhibitory signalling events.
Fig. 2: Skeletal muscle during cancer cachexia.
Fig. 3: Proposed AMPK signalling network in white adipose tissue during cancer cachexia.

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Acknowledgements

H.T.L. and M.D.G. are funded as part of the CANCAN team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100022) and the National Cancer Institute (1 OT2 CA278685-01). L.S. received funding from The Novo Nordisk Foundation (grants NNF16OC0023418, NNF18OC0032082, NNF20OC0063577), Independent Research Council Denmark (DFF-4004-00233, 0169-00013B, 0169-00060B), the Danish Cancer Society (R302-A17605), and the Carlsberg Foundation (#CF21-0369). M.R. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (#949017), the Helmholtz Association – Initiative and Networking Fund, the European Foundation for the Study of Diabetes (EFSD)/ Novo Nordisk Foundation Future Leaders Award, and the German Center for Diabetes Research (DZD).

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Authors and Affiliations

  1. Division of Endocrinology, Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Henning Tim Langer & Marcus DaSilva Goncalves

  2. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany

    Henning Tim Langer

  3. Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany

    Maria Rohm

  4. Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany

    Maria Rohm

  5. German Center for Diabetes Research (DZD), Neuherberg, Germany

    Maria Rohm

  6. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Lykke Sylow

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Correspondence to Henning Tim Langer.

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During revision of the manuscript H.T.L. started to work for Boehringer Ingelheim GmbH & Co. KG. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks Gregory Steinberg, who co-reviewed with Andrew Mikhail; David Carling; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Langer, H.T., Rohm, M., Goncalves, M.D. et al. AMPK as a mediator of tissue preservation: time for a shift in dogma?. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00992-y

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